Design, synthesis and SAR of a novel series of benzimidazoles as potent NPY Y5 antagonists

A novel class of benzimidazole NPY Y5 receptor antagonists was prepared exploiting a privileged spirocarbamate moiety. The structure-activity relationship of this series and efforts to achieve a profile suitable for further development and an appropriate pharmacokinetic profile in rat are described. Optimisation led to the identification of the brain penetrant, orally bioavailable Y5 antagonist 9b which significantly inhibited the food intake induced by a Y5 selective agonist with a minimal effective dose of 30mg/kg po.     

DE-loop mutations affect ��2 microglobulin stability, oligomerization, and the low-pH unfolded form

β2 microglobulin (β2m) is the light chain of class‐I major histocompatibility complex (MHC‐I). Its accumulation in the blood of patients affected by kidney failure leads to amyloid deposition around skeletal joints and bones, a severe condition known as Dialysis Related Amyloidosis (DRA). In an effort to dissect the structural determinants of β2m aggregation, several β2m mutants have been previously studied. Among these, three single‐residue mutations in the loop connecting strands D and E (W60G, W60V, D59P) have been shown to affect β2m amyloidogenic properties, and are here considered. To investigate the biochemical and biophysical properties of wild‐type (w.t.) β2m and the three mutants, we explored thermal unfolding by Trp fluorescence and circular dichroism (CD). The W60G mutant reveals a pronounced increase in conformational stability. Protein oligomerization and reduction kinetics were investigated by electrospray‐ionization mass spectrometry (ESI‐MS). All the mutations analyzed here reduce the protein propensity to form soluble oligomers, suggesting a role for the DE‐loop in intermolecular interactions. A partially folded intermediate, which may be involved in protein aggregation induced by acids, accumulates for all the tested proteins at pH 2.5 under oxidizing conditions. Moreover, the kinetics of disulfide reduction reveals specific differences among the tested mutants. Thus, β2m DE‐loop mutations display long‐range effects, affecting stability and structural properties of the native protein and its low‐pH intermediate. The evidence presented here hints to a crucial role played by the DE‐loop in determining the overall properties of native and partially folded β2m.     

Thieno[3,2-c]pyrazoles: A novel class of Aurora inhibitors with favorable antitumor activity

A novel series of 3-amino-1H-thieno[3,2-c]pyrazole derivatives demonstrating high potency in inhibiting Aurora kinases was developed. Here we describe the synthesis and a preliminary structure–activity relationship, which led to the discovery of a representative compound (38), which showed low nanomolar inhibitory activity in the anti-proliferation assay and was able to block the cell cycle in HCT-116 cell line. This compound demonstrated favorable pharmacokinetic properties and good efficacy in the HL-60 xenograft tumor model.     

Allometric constraints and competition enable the simulation of size structure and carbon fluxes in a dynamic vegetation model of tropical forests (LM3PPA‐TV)

Tropical forests are a key determinant of the functioning of the Earth system, but remain a major source of uncertainty in carbon cycle models and climate change projections. In this study, we present an updated land model (LM3PPA‐TV) to improve the representation of tropical forest structure and dynamics in Earth system models (ESMs). The development and parameterization of LM3PPA‐TV drew on extensive datasets on tropical tree traits and long‐term field censuses from Barro Colorado Island (BCI), Panama. The model defines a new plant functional type (PFT) based on the characteristics of shade‐tolerant, tropical tree species, implements a new growth allocation scheme based on realistic tree allometries, incorporates hydraulic constraints on biomass accumulation, and features a new compartment for tree branches and branch fall dynamics. Simulation experiments reproduced observed diurnal and seasonal patterns in stand‐level carbon and water fluxes, as well as mean canopy and understory tree growth rates, tree size distributions, and stand‐level biomass on BCI. Simulations at multiple sites captured considerable variation in biomass and size structure across the tropical forest biome, including observed responses to precipitation and temperature. Model experiments suggested a major role of water limitation in controlling geographic variation forest biomass and structure. However, the failure to simulate tropical forests under extreme conditions and the systematic underestimation of forest biomass in Paleotropical locations highlighted the need to incorporate variation in hydraulic traits and multiple PFTs that capture the distinct floristic composition across tropical domains. The continued pressure on tropical forests from global change demands models which are able to simulate alternative successional pathways and their pace to recovery. LM3PPA‐TV provides a tool to investigate geographic variation in tropical forests and a benchmark to continue improving the representation of tropical forests dynamics and their carbon storage potential in ESMs.     

Modeling leaf senescence of deciduous tree species in Europe

Autumnal leaf senescence signals the end of photosynthetic activities in temperate deciduous trees and consequently exerts a strong control on various ecological processes. Predicting leaf senescence dates (LSD) with high accuracy is thus a prerequisite for better understanding the climate–ecosystem interactions. However, modeling LSD at large spatial and temporal scales is challenging. In this study, first, we used 19972 site‐year records (848 sites and four deciduous tree species) from the PAN European Phenology network to calibrate and evaluate six leaf senescence models during the period 1980–2013. Second, we extended the spatial analysis by repeating the procedure across Europe using satellite‐derived end of growing season and a forest map. Overall, we found that models that considered photoperiod and temperature interactions outperformed models using simple temperature or photoperiod thresholds for Betula pendula, Fagus sylvatica and Quercus robur. On the contrary, no model displayed reasonable predictions for Aesculus hippocastanum. This inter‐model comparison indicates that, contrary to expectation, photoperiod does not significantly modulate the accumulation of cooling degree days (CDD). On the other hand, considering the carryover effect of leaf unfolding date could promote the models’ predictability. The CDD models generally matched the observed LSD at species level and its interannual variation, but were limited in explaining the inter‐site variations, indicating that other environmental cues need to be considered in future model development. The discrepancies remaining between model simulations and observations highlight the need of manipulation studies to elucidate the mechanisms behind the leaf senescence process and to make current models more realistic.     

Cumulative biomass curves describe past and present conditions of Large Marine Ecosystems

Implementing the Ecosystem Approach in marine ecosystems is moving from preliminary steps—dedicated to defining the optimal features for indicators and developing efficient indicator frameworks—towards an operational phase where multisector marine management decisions are executed using this information. Within this operational context, emergent ecosystem properties are becoming quite promising as they have been demonstrated to be globally widespread and repeatable, and to be quite effective in detecting significant state variations of complex systems. Biomass accumulation across TLs (CumB‐TL) combines two important emergent properties of an ecosystem (energy flow, in terms of transfer efficiency, and storage, expressed as biomass), both amenable to detecting rapid ecosystem change. However, for further application, it is crucial to understand which types of drivers an indicator is sensitive to and how robust it is in relation to modifications of the external conditions and/or the system state. Here we address some outstanding questions of these CumB‐TL curves related to their sensitivity to various drivers by carrying out a global scale assessment (using data from 62 LMEs) over six decades (1950–2010). We confirm the consistency of the S‐pattern across all the LMEs, independent from latitude, ecosystem, environmental conditions, and stress level. The dynamics of the curve shape showed a tendency to stretch (i.e. decrease of steepness), in the presence of external disturbance and conversely to increase in steepness and shift towards higher TL in the case of recovery from stressed conditions. Our results suggest the presence of three main types of ecosystem dynamics, those showing an almost continuous increase in ecological state over time, those showing a continuous decrease in ecological state over time, and finally those showing a mixed behaviour flipping between recovering and degrading phases. These robust patterns suggest that the CumB‐TL curve approach has some useful properties for use in further advancing the implementation of the Ecosystem Approach, allowing us to detect the state of a given marine ecosystem based on the dynamics of its curve shape, by using readily available time series data. The value of being able to identify conditions that might require management actions is quite high and, in many respects, represents the main objective in the context of an Ecosystem Approach, with large applications for detecting and responding to global changes in marine ecosystems.     

Spinal muscular atrophy with respiratory distress type 1: Clinical phenotypes,molecular pathogenesis and therapeutic insights

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder caused by mutations in the IGHMBP2 gene, which encodes immunoglobulin μ‐binding protein 2, leading to progressive spinal motor neuron degeneration. We review the data available in the literature about SMARD1. The vast majority of patients show an onset of typical symptoms in the first year of life. The main clinical features are distal muscular atrophy and diaphragmatic palsy, for which permanent supportive ventilation is required. No effective treatment is available yet, but novel therapeutic approaches, such as gene therapy, have shown encouraging results in preclinical settings and thus represent possible methods for treating SMARD1. Significant advancements in the understanding of both the SMARD1 clinical spectrum and its molecular mechanisms have allowed the rapid translation of preclinical therapeutic strategies to human patients to improve the poor prognosis of this devastating disease.